United States Patent (19) 11 Patent Number: 4,780,463 Sunshine et al. (45) Date of Patent: Oct. 25, 1988 (54). ANALGESIC, ANTI-INFLAMMATORY AND Ailments of the Musculoskeletal Apparatus), Investiga SKELETAL MUSCLE RELAXANT tion Medica Internactional, pp. 475-478, (1983), and COMPOSITIONS COMPRISING English translation thereof. NON-STEROIDAL ANTI-NFLAMMATORY Socialist Republic of Romania Description of Inven DRUGS AND MUSCULOSKELETAL tion, 82,717, copy of patent and English translation RELAXANTS AND METHODS OF USING thereof. SAME Rego, "Mio-Relaxantes No Tratamento Das Lom 75 Inventors: Abraham Sunshine, New York; balgias Aguda E Da Lombo-Ciaticas Recentes', Mus Eugene M. Laska, Larchmont; cle Relaxants in the Treatment of Acute Lumbalgias Carole E. Siegel, Mamaroneck, all of and Recent Lumbo-Sciatica Cases, Acta N.Y. Reumatologica Portuguesa, II, 2:363-364, (1974), copy of the original and English translation thereof. 73 Assignee: Analgesic Associates, Larchmont, Schror, "Analgetisch-antiphlogistische Therapie Von N.Y. Schmerzzustanden des Bewegungsapparates', Anal 21 Appl. No.: 114,751. gesic-Antiphlogistic Therapy of Locomotor System Pain), Therapiewoche, 28, 5657-5663, (1978), copy of the 22 Filed: Oct. 30, 1987 original and English translation thereof. Schar, "Medikamentose Behandling von Lumboishial Related U.S. Application Data gien', Drug Treatment of the Lumbago-Sciatic Syn 60 Division of Ser. No. 815,502, Jan. 2, 1986, Pat. No. drome, Schweiz. Rundschau Med., (Praxis), vol. 68, No. 4,722,938, which is a continuation of Ser. No. 686,380, 5, pp. 141-142, (Jan. 30, 1979), copy of original article Dec. 26, 1984, abandoned. and English translation thereof. 51) int. Cl.' ..................... A61K 31/19; A61K 31/44; Kolodny and Klipper, "Bone and Joint Diseases in the A61K 3/54; A61K 31/195; A61K 31/205 Elderly', Hospital Practice, pp. 91-101, (Nov., 1976). 52 U.S. Cl. ................................. 514/226.5; 514/279; Nascimento, "Use of an Association Containing an . 514/556; 514/561; 514/570 Analgeisc, a Muscle Relaxant and Vitamin B Complex 58 Field of Search ............... 514/226, 279, 556, 561, in Degenerative Joint Diseases, Extra-Articular Rheu 514A570 matic Ailments and Traumatic Afflications, F med, 56) References Cited (BR), 83(3):361-363, (1981), original article and English translation thereof. U.S. PATENT DOCUMENTS Repschlaeger and McPherson, "Classification, Mecha 4,722,938 2/1988 Sunshine et al. .................... 514/479 nism and Management of Headache', Clinical Phar FOREIGN PATENT DOCUMENTS mary, vol. 3, pp. 139-150, (Mar.-Apr. 1984). 22529 12/1971 France . Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Burns, Doane, Swecker & OTHER PUBLICATIONS Mathis Armas & Valencia, "Eficacia terapeutica de la associa 57 ABSTRACT cion naproxen-carisoprodoi en ciertas enfermedader musculoesqueleticas', Therapeutic Effectiveness of Novel pharmaceutical analgesic, anti-inflammatory and Naproxen-Carisoprodol Association in Certain Muscu skeletal muscle relaxant compositions and methods of loskeletal Disorders, in Investigation Medica Interna using same comprising an analgesically and anti-inflam cional, pp. 350-356, (1983), and English translation matory effective amount of at least one non-steroidal thereof. anti-inflammatory drug other than aspirin, acetamino Goti & Valencia, "Caracterizacion clinica de una nueva phen and phenacetin, in combination with an effectiv asociacion (naproxen-carisoprodol) en padecimientos amount of a skeletal muscle relaxant. del aparato musculoesqueletico', Clinical Description of a New Association (Naproxen.--Carisoprodol) in 14 Claims, No Drawings 4,780,463 1. 2 is a conventional non-narcotic analgesic with anti-in ANALGESIC, ANTI-NFLAMMATORY AND flammatory and antipyretic activity. The most common SKELETAL MUSCLE RELAXANT adverse reactions associated with the use of aspirin in COMPOSITIONS COMPRISING this product have been gastrointestinal, including nau NONSTEROIDAL ANTI-NFLAMMATORY 5 Sea, vomiting, gastritis, occult bleeding, constipation DRUGS AND MUSCULOSKELETAL RELAXANTS and diarrhea. Allergic type reactions associated with AND METHODS OF USING SAME aspirin may also involve the respiratory tract and skin. Another commercial skeletal muscle relaxant formu This application is a divisional, of application Ser. lation is Parafon Forte (R) by McNeil Pharmaceutical. No. 815,502, filed Jan. 2, 1986, U.S. Pat. No. 4,722,938 10 Parafon Forte contains 250 mg chlorzoxazone and 300 which is a continuation of U.S. Ser. No. 686,380 filed mg acetaminophen. Chlorzoxazone is a centrally-acting Dec. 26, 1984, now abandoned. agent which does not directly relax tense skeletal mus cles in man. Acetaminophen, a nonsalicylate analgesic, BACKGROUND OF THE INVENTION is a conventional non-narcotic analgesic with anti 1. Field of the Invention 15 pyretic activity. The present invention relates generally to novel phar Robaxisal (R) by A.H. Robins Company, Inc. is an maceutical compositions of matter comprising one or other commercial muscle relaxant formulation which more non-steroidal anti-inflammatory drugs in combi contains 400 mg methocarbamol and 325 mg aspirin. nation with at least one skeletal muscle relaxant, and to The mechanism of action of methocarbamol in humans methods of using said compositions in the treatment of 20 has not been established, but may be due to general a variety of skeletal muscle disorders including skeletal central nervous system depression. Methocarbamol muscle spasms, certain orthopedic conditions, disk syn does not directly relax tense skeletal muscles in man. dromes, low back pain and the like. Adverse reactions that have been associated with aspi 2. Description of the Prior Art rin in this formulation include: nausea and other gastro Centrally acting skeletal muscle relaxants are gener 25 intestinal discomfort, gastritis, gastric erosion, vomit ally prescribed either as single agents or as components ing, constipation, diarrhea, angioedema, asthma, rash, of combination products. The Food and Drug Adminis pruritis and urticaria. tration has approved indications for these medications Norgesic (E) and Norgesic (R) Forte are commercial as adjuncts to rest and physical therapy for relief of products by Riker Laboratories, Inc. that contain a acute, painful musculoskeletal problems. Clinically, the 30 muscle relaxant, aspirin and caffeine. The specific for mild pain associated with the majority of cases of minor mulation for Norgesic is 25 mg orphenadrine citrate, muscle strains and minor injuries is self limiting. Most 385 mg aspirin and 30 mg caffeine. Norgesic Forte patients usually respond rapidly to rest. An anti-inflam contains 50 mg orphenadrine citrate, 770 mg aspirin and matory drug may be useful when there is considerable 60 mg caffeine. Orphenadrine citrate is 2-dime tissue damage and edema. On the other hand, severe 35 thylaminoethyl 2-methylbenzhydryl ether citrate. The musculoskeletal strains and sprains, trauma, and cervi common side effects and concerns associated with the cal or lumbar radiculopathy as a consequence of degen use of aspirin occur with the use of Norgesic and Nor erative osteoarthritis, herniated disk, spondylitis or lam gesic Forte as well. TABLE I Some Combination Products Containing a Skeletal Muscle Relaxant TYPICAL DOSAGE CONTENTS OF A SINGLE TABLET PRESENTED AS TRADENAME SKELETAL MUSCLE RELAXANT ADDITIONAL INGREDIENTS NO. OF TABLETS SOMA COMPOUND Carisoprodol 200 mg aspirin 325 mg 1-2 SOMA COMPOUND Carisoprodol 200 mg aspirin 325 mg WITH CODEINE codeine PO4. 16 ng 1-2 PARAFON FORTE Corzoxazone 250 mg acetaminophen 300 mg 1-2 ROBAXISAL Methocarbano 400 mg aspirin 325 mg 2 NORGESIC Orphenadrine 25 mg aspirin 385 mg 1-2 Citrate caffeine 30 mg NORGESICFORTE Orphenadrine 50 mg aspirin 770 mg -1 Citrate caffeine 60 mg inectomy, often cause moderate or severe and more chronic painful skeletal muscle spasm. The principal At the present time, one commercial product, Para symptoms include local pain, tenderness on palpation, 55 fon Forte, a skeletal muscle relaxant formulation con increased muscle consistency and limitation of motion. taining acetaminophen, will be the subject of a hearing For these patients skeletal muscle relaxants alone or in granted by the Commissioner of Food and Drugs on a combination with an analgesic are frequently pre proposal to withdraw approval of its new drug applica scribed. Results of some studies have suggested that a tion sometime in 1985. The Director of the Bureau of formulation of a muscle relaxant and an analgesic pro Drugs of the FDA in a notice published in the Federal vides greater benefit in patients with acute musculoskel Register, 1982, 47 F.R. 22599 concluded that he was etal problems than similar doses of an analgesic alone. unaware of any adequate and well-controlled clinical Table I lists several commercial combinations avail investigation conducted by experts qualified by scien able. A current commercial muscle relaxant formulation tific training and experience ... that demonstrates the is Soma (R) Compound by Carter-Wallace, Inc. which 65 effectiveness of Parafon Forte. The present position of contains 200 mg carisoprodol and 325 mg aspirin. Cari the Commissioner of Food and Drugs is set forth below soprodol is a centrally-acting muscle relaxant that does Federal Register, 1984, 49(200): 48212-482.14): not directly relax tense skeletal muscles in man. Aspirin 4,780,463 3 4 Approval of this NDA will be withdrawn unless Another object of the present invention is to provide there